Conjugates of monoclonal antibodies (MAbs) with drugs or toxins have been investigated for many years as a potential approach to delivering these agents more specifically to cancers. One such compound, Mylotarg(, a conjugate of the anti-CD33 antibody with the highly potent cytotoxic drug, calicheamicin, has gained FDA approval for treatment of CD33-positive acute myeloid leukemia in patients over age 60 in first relapse. Other drug-MAb conjugates are currently in development for the treatment of various solid tumors. Although some have suggested that Mab conjugates of conventional anticancer drugs, such as doxorubicin (Dox) would not have adequate potency to elicit a significant therapeutic effect, we have accumulated a large body of evidence showing that the correct antigen-antibody targeting system can result in a highly effective Dox-immunoconjugate. CD74 is a type-ll transmembrane chaperone molecule that associates with HLA-DR, inhibiting binding of antigenic peptides to the class-ll antigen presentation structure. It is expressed on the surface of several types of tumor cells (e.g., NHL, MM, melanoma and RCC cells) and directs transport from the surface to an endosomal compartment within the cell. We have shown potent activity of antibody conjugates of radionuclides against CD74+ B cells, using the rapidly internalizing LL1 antibody to target CD74 labeled with Auger electron emitters. These results provided the impetus to test the LL1-anti-CD74 MAb for drug delivery. Doxorubicin, a key drug in the management of NHL affords many advantages for drug-conjugate therapy including: (a) water-soluble nature and therefore readily compatible with aqueous protein solutions; (b) having several chemically reactive groups; (c) possessing several mechanisms of action, including inhibition of topoisomerase II, intercalation into DNA, and disrupting on cell membranes. Therapeutic results with LL1-Dox in a systemic NHL xenograft model have been outstanding (see preliminary results and appended manuscript). Non-Hodgkin's lymphoma (NHL) is the 5th most common cancer in the U.S. and accounts for 5% of all cancer-related deaths per year. The 5-year cure rate is only 50%. These tumors are known to express significant amounts of the CD74 antigen. NHL might best respond to a specific targeting approach using a drug-Ab conjugate, due to its widely disseminated nature and the relative accessibility of cancer cells to systemically administered agents. In addition, the greater inherent sensitivity of hematopoietic tumors, the natural course of this disease with cells growing out of control and terminally outnumbering normal B cells, offers the chance of delivering a much higher ratio of injected drug-AB specifically to diseased cells, as compared to normal cells. This proposal will therefore address the utility of an LL1-Dox immunoconjugate for treatment of disseminated NHL using several established preclinical models and primary NHL biopsy specimens. We will also address several novel biological questions including (a) the possibility of overcoming multidrug resistance (typically expressed by ~60% of refractory NHL patients) by delivering Dox directly with an antibody, and (b) overcoming cardiotoxicity associated with the administration of free doxorubicin. [unreadable] [unreadable]